Evidence will be sought for the site(s) and neurotransmitter mechanism(s) of action of indoleamine- and phenethylamine-type hallucinogenic drugs. LSD, DOM, mescaline, and DMT will be examined on FR-40 operant behavior for the pause-type pattern, extending previous studies. Lesions of regional 5-HT neurons will be accomplished by infusing the neurotoxin 5,7-DHT into portions of the limbic system and these rats will be tested for changes in the dose-response for the pause effect produced by the hallucinogenic drugs. Brain DA, NE, 5HT and their metabolites will be measured to determine the extent and specificity of the lesions. The influence of 5HT agonists, 5-HT antagonists and the non-hallucinogenic LSD analogue lisuride on the hallucinogenic pause, as well as for their effects alone on FR40 responding, will be explored in other animals. Interactions with other non-hallucinogenic psychoactive agents (e.g., depressants, stimulants) will be done as controls. Tolerance development with various repeated doses of the hallucinogens, as well as cross-tolerance, for the FR-40 pause will be characterized. Effects of pretreatments with 5,7-DHT, PCPA and 5HT antagonists will be studied to determine any alterations in the pattern of tolerance development. Since the FR-40 program cannot distinguish hallucinogens from other 5-HT agonists, other behavioral tests will be included: orienting motor activity, accommodated motor activity, "rage" response of Long-Evans hooded rats, discriminated instrumental avoidance examining late responses, and a variable interval schedule of two-lever choice behavior for food reinforcement based on discrimination of visual or auditory stimulus patterns. Rectal temperatures of rats and rabbits in response to the drugs will also be determined. These additional tests may allow us to select out the hallucinogenic 5-HT agonists. Also they may afford a better opportunity to examine the hypothesis that 5-HT agonistic activity of the hallucinogenic drugs exerted at certain brain sites causes an imbalance in activities of various forebrain 5-HT systems that is of paramount importance for the expression of their major pharmacological effects.